Leptospirosis is among the most common zoonotic diseases worldwide, affecting people in industrialized countries but taking a far higher toll in developing countries. This disease is caused by spirochetes of the genus Leptospira, which colonize renal tubules of asymptomatic mammalian reservoir hosts for weeks, months, even years. Annually, millions of cases occur worldwide, with case fatality rates in identifiable cases reported to range up to 25%. However, most cases of leptospiral infection are mild or asymptomatic. Severe manifestations occur in ~1-10% of patients who come to medical attention, depending on locale, with variable manifestations culminating in jaundice, renal failure, and, most ominously, pulmonary hemorrhage. The fulminant hemorrhagic form of leptospirosis can closely mimic a number of viral hemorrhagic fevers caused by potential bioterrorism agents. This project hypothesizes, on the basis of a mouse model of severe leptospirosis, that Toll-like Receptor 4 (TLR4) is critical for protection from severe leptospirosis and that TLR4 polymorphisms that alter the function of TLR4 in humans will be overrepresented in severe leptospirosis patients compared to patients with non-severe leptospirosis and the general population. To test this hypothesis, the specific aim of this project is to determine the association of TLR4, TLR2, and MD-2 genotypes with risk for severe leptospirosis. We have established study sites in Sao Paulo, Brazil, where we have demonstrated that leptospirosis is common and there are frequent hospital admissions for severe disease. The study design will be to genotype patients in three groups: Severe leptospirosis cases, uncomplicated leptospirosis cases, and people with no evidence of past leptospiral infection (general population). We will obtain blood samples from these and control patients that will permit us to genotype and sequence TLR4, TLR-2, MD-2 and other genes of the innate immune system in these patient groups. The results are expected to determine whether uncommon innate immune gene polymorphisms are overrepresented in severe leptospirosis patients compared to the control groups, and provide the basis for future mechanistic experiments to determine the role of innate immunity in protection against severe leptospirosis. [unreadable] [unreadable] [unreadable] [unreadable]